Adrenergic Pharmacology

⚗️ NE synthesis, release, clearance

Tyrosine → (tyrosine hydroxylase, rate‑limiting) → DOPA → (DOPA decarboxylase) → dopamine → (DA β‑hydroxylase) → norepinephrine
Storage: NE packaged into synaptic vesicles; mobile pool vs. granule‑bound pool
Release: action potential → voltage‑gated Ca²⁺ influx → vesicle fusion → exocytosis
Termination:
- Primary: NE reuptake via Na⁺/NE cotransporter (presynaptic)
- Metabolism: MAO‑A (intraneuronal) & COMT (synaptic cleft)
Regulation: presynaptic α₂‑autoreceptors inhibit further NE release (negative feedback)

Reuptake blockade (cocaine, TCAs) prolongs NE action; MAO‑A inhibition increases cytosolic NE.

Receptor	G-protein	Effector	Key locations / effects
α₁	Gq	↑ PLC → IP₃/DAG → ↑Ca²⁺	Vascular smooth muscle (vasoconstriction), bladder sphincter, radial muscle (mydriasis)
α₂	Gi	↓ adenylyl cyclase → ↓cAMP	Presynaptic terminals (inhibits NE release), platelets (aggregation), pancreas (↓ insulin)
β₁	Gs	↑ adenylyl cyclase → ↑cAMP	Heart (↑ HR, contractility, conduction), kidney (↑ renin)
β₂	Gs	↑ adenylyl cyclase → ↑cAMP	Vascular/ bronchial smooth muscle (relaxation), uterus, liver (glycogenolysis)
β₃	Gs	↑ adenylyl cyclase → ↑cAMP	Detrusor (relaxation) — overactive bladder target
D₁ (periph)	Gs	↑ adenylyl cyclase → ↑cAMP	Renal/mesenteric vessels → vasodilation ↑ RBF, ↑ GFR

α₁ activation: ↑ systemic vascular resistance (TPR), ↑ diastolic pressure, ↑ afterload
β₂ activation: vasodilation, bronchodilation, decreased diastolic pressure, tremor
β₁ sensitivity: low doses of mixed agonists produce β‑effects; higher doses α‑effects dominate

α₁ agonists (phenylephrine): vasoconstriction → ↑BP, reflex bradycardia. Uses: nasal decongestant, mydriasis, hypotension
α₂ agonists (clonidine, methyldopa): central presynaptic stimulation → ↓ sympathetic outflow. Use: mild‑moderate hypertension
β‑agonists:
- Isoproterenol (β₁≈β₂): ↓BP (vasodilation), ↑HR
- Dobutamine (β₁>β₂): inotropic support in CHF
- Selective β₂: albuterol, salmeterol (asthma), terbutaline (tocolysis)
- β₃ agonist: mirabegron (overactive bladder)
Norepinephrine (α₁, α₂, β₁): potent vasoconstriction, ↑BP, reflex bradycardia. Uses: hypotension, shock
Epinephrine:
- Low dose: β₁+β₂ → vasodilation, ↑HR, ↓diastolic
- High dose: α₁ effect dominates → vasoconstriction, ↑BP
- Metabolic: glycogenolysis, gluconeogenesis, lipolysis
Epinephrine reversal: after α₁‑blockade, high‑dose epinephrine produces hypotension (unopposed β₂ vasodilation)

Epinephrine is first‑line for anaphylaxis; norepinephrine is not used for anaphylaxis.

Releasers: displace NE from mobile pool (amphetamines, tyramine)
Tyramine: normally metabolized by MAO‑A in gut/liver; MAOI → hypertensive crisis
Amphetamine: central DA/NE/5HT release → psychostimulation
Reuptake inhibitors: cocaine, tricyclic antidepressants (TCAs) – prolong NE action
Indirect agonists require intact innervation; denervated tissues are unresponsive

MAO‑A metabolizes NE, 5‑HT, tyramine; MAO‑B primarily in brain (DA).

Decrease TPR → ↓ mean BP; reflex tachycardia & salt/water retention
Nonselective: phentolamine (competitive), phenoxybenzamine (noncompetitive) — used in pheochromocytoma
Selective α₁: prazosin, doxazosin, terazosin, tamsulosin — BPH, hypertension
Selective α₂: mirtazapine (antidepressant)

α‑blockers may cause orthostatic hypotension and reflex tachycardia.

β₁ blockade: ↓ HR, contractility, CO, renin release
β₂ blockade: bronchospasm, vasospasm, ↓ glycogenolysis, ↑ LDL/TG
Cardioselective (β₁): atenolol, metoprolol, acebutolol – safer in asthma/PVD
ISA (partial agonist): pindolol, acebutolol – less bradycardia, fewer lipid changes
Combined α+β: labetalol, carvedilol (CHF, hypertensive emergencies)
K⁺‑channel blockade + β: sotalol (antiarrhythmic)
General uses: angina, HTN, post‑MI, migraine, thyrotoxicosis, tremor, glaucoma (timolol)

Beta‑blocker withdrawal: upregulation → rebound tachycardia/hypertension – taper slowly.

Drug	β₁‑selective	ISA	Lipid effects
Acebutolol	✓	✓	minimal
Atenolol	✓	✗	↑↑
Metoprolol	✓	✗	↑↑
Pindolol	✗	✓	minimal
Propranolol	✗	✗	↑↑

Glucagon: positive inotropy/chronotropy via Gs‑coupled glucagon receptors – used in β‑blocker overdose
Epinephrine reversal: α₁‑blocker unmasks β₂‑mediated vasodilation → hypotension
Pheochromocytoma: nonselective α‑blockade (phenoxybenzamine) before surgery
Fenoldopam: D₁ agonist – used for severe hypertension (renal vasodilation)
Dobutamine: β₁ > β₂, increases CO with less vasoconstriction than dopamine
β₂ agonists: terbutaline – tocolysis; albuterol – asthma; mirabegron – overactive bladder

Beta‑2 blockade can precipitate bronchospasm – avoid non‑selective β‑blockers in asthma.